Principal Investigator: Chen, Lu Summary Our research focuses on uncovering the molecular mechanisms of a form of non-Hebbian synaptic plasticity, namely homeostatic synaptic plasticity. In contrast to the self-reinforcing nature of Hebbian plasticity, homeostatic plasticity operates under different rules as a ?corrective? mechanism to prevent run-away Hebbian plasticity. Compared to Hebbian plasticity, the molecular and cellular mechanisms underlying homeostatic synaptic plasticity is much less understood, and their implication in neuropsychiatric disorders is largely unexplored. Work from our labs in the past years show that retinoic acid (RA) signaling, a major signaling pathway mediating homeostatic synaptic plasticity, is severely impaired in the absence of FMRP expression, resulting in a lack of homeostatic plasticity in both mouse and human FXS neurons. Moreover, we demonstrate that under a more natural, enriched environment, compromised homeostatic synaptic plasticity in adult mice induces run away Hebbian plasticity as manifested by greatly enhanced LTP and diminished LTD. As a behavioral consequence, animals with defective homeostatic plasticity exhibit enhanced learning but reduced behavioral flexibility when raised in enriched environment. Together, our work establishes a link between synaptic RA signaling, homeostatic plasticity and cognitive function, and suggests that impaired homeostatic plasticity may contribute to cognitive deficits in FXS. The goal of the proposed research project is to gain further understanding of the molecular and cellular mechanisms of RA-dependent homeostatic plasticity. Specifically, we will focus on three aspects of RA signaling in the context of homeostatic synaptic plasticity: the trans-synaptic cell adhesion molecule neurexins, the BDNF-TrkB retrograde signaling, and the functional interaction between FMRP and RA receptor RAR?. Together, results from this proposed study will identify new candidate molecular tools for investigating in vivo function of homeostatic synaptic plasticity, and also provide insight into discovering new drug targets for treating FXS and potentially other mental disorders. Relevance This project will investigate molecular mechanisms through which synaptic RA signaling regulates synaptic strength in a homeostatic manner. Recent studies using FXS model mice and human FXS patient neurons establish that defective RA-dependent homeostatic synaptic plasticity is a major synaptic dysfunction phenotype associated with fragile-x syndrome. Thus, uncovering additional molecular players critically involved in homeostatic plasticity will provide the opportunity to discover new drug targets for treating FXS and other forms of mental illness in which circuit maladaptation due to compromised homeostatic plasticity is a major contributor to disease symptoms. PHS 398/2590 (Rev. 11/07) Page 1 Summary